title: Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation.
abstract: Phagophore maturation is a key step in the macroautophagy pathway, which is critical in many important physiological and pathological processes. Here we identified Drosophila N-ethylmaleimide-sensitive fusion protein 2 (dNSF2) and soluble NSF attachment protein (Snap) as strong genetic modifiers of mutant CHMP2B, an ESCRT-III component that causes frontotemporal dementia and autophagosome accumulation. Among several SNAP receptor (SNARE) genes, Drosophila syntaxin 13 (syx13) exhibited a strong genetic interaction with mutant CHMP2B. Knockdown of syntaxin 13 (STX13) or its binding partner Vti1a in mammalian cells caused LC3-positive puncta to accumulate and blocks autophagic flux. STX13 was present on LC3-positive phagophores induced by rapamycin and was highly enriched on multilamellar structures induced by dysfunctional ESCRT-III. Loss of STX13 also caused the accumulation of Atg5-positive puncta and the formation of multilamellar structures. These results suggest that STX13 is a genetic modifier of ESCRT-III dysfunction and participates in the maturation of phagophores into closed autophagosomes.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, 01605 USA.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, 01605 USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Danqiong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Sweeney
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, 01605 USA.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C543046:CHMP2B protein, Drosophila; C503812:CHMP2B protein, human; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008164:Luminescent Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C498738:Nsf2 protein, Drosophila; D050765:Qa-SNARE Proteins; D033921:Vesicular Transport Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins